Cardiovascular disease (CVD) is the number one cause of death globally. More people die annually from CVD than from any other cause. Smoking, hypertension, high LDL cholesterol, low HDL cholesterol and diabetes mellitus (DM) are the five major risk factors for CVD. Diabetes is associated with an increased risk of atherosclerosis, which may result in coronary artery disease (CAD) (A. Pandolfi, et al., “Chronic hyperglycemia and nitric oxide bioavailability play a pivotal role in proatherogenic vascular modifications,” Genes & Nutrition (2007) 2 (2): 195-208). Physiological impairments that link DM with a marked increase in atherosclerotic vascular disease include platelet hyper-reactivity, a tendency for negative arterial remodeling, impaired fibrinolysis, increased inflammation, and endothelial dysfunction.
Endothelial dysfunction, present at disease onset, may be the cause of atherogenesis that is present throughout the course of DM and associated with late-stage adverse outcomes (Panwar, et al., “Atherothrombotic risk factors & premature coronary heart disease in India: A case-control study,” Indian J. Med. Res. (July 2011) 134: 26-32). The endothelial dysfunction results from reduced bioavailability of the vasodilator nitric oxide (NO) mainly due to accelerated NO degradation by reactive oxygen species (J. A. Beckman, “Pathophysiology of Vascular Dysfunction in Diabetes,” Cardiology Rounds (December 2004) Volume 8, Issue 10). A currently favored hypothesis is that oxidative stress, through a single unifying mechanism of superoxide production, is the common pathogenic factor leading to insulin resistance, β-cell dysfunction, impaired glucose tolerance (IGT) and ultimately to Type 2 DM (T2DM). Furthermore, this mechanism has been implicated as the underlying cause of both the macrovascular and microvascular complications associated with Type 2 DM. It follows that therapies aimed at reducing oxidative stress would benefit both patients with T2DM and those at risk for developing diabetes (Potneza, et al., “Endothelial Dysfunction in Diabetes: From Mechanism to Therapeutic Targets,” Current Medicinal Chemistry (2009) 16: 94-112; S. E. Inzucchi, “Oral Antihyperglyccmic Therapy for Type 2 Diabetes. Scientific Review and Clinical Applications,” Journal of American Medical Association (Jan. 16, 2002—Vol 287, No. 3, pp. 360-372; and Wright, et al., “Oxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia,” Int. J. Clin. Pract. (2006 March) 60(3): 308-314).
Many natural product compositions possess potent antioxidant, anti-inflammatory and cardio-protective properties and are used by patients with increased risk of cardiovascular morbidity and mortality in order to treat or prevent disease and/or reduce symptoms. Among them, Phyllanthus emblica, syn. Emblica officinalis Gaertn., the Indian gooseberry (PE, “Amla”) is widely used in Indian medicine for the treatment of various diseases. There are studies which show significant anti-hyperglycaemic and lipid lowering effects of PE in diabetic patients. In in-vitro and animal studies, PE demonstrates potent antioxidant effects against several test systems such as superoxide radical and hydroxyl radical scavenging action, and in systemic augmentation of antioxidant enzymes in animals (Antony, et al., “A pilot clinical study evaluate the effect of Emblica officinalis extract (Amlamax™) on markers of systemic inflammation and dyslipidemia,” Indian J. Clin. Biochemistry (2008) 23(4): 378-381).
In addition, Shilajit is an herbo-mineral drug, which oozes out from a special type of Himalayan mountain rocks in the peak summer months. It is found at high altitudes ranging from 1000-5000 meters. The active constituents of Shilajit contain dibenzo-alpha-pyrones, fulvic acids and related metabolites, small peptides (constituting non-protein amino acids), some lipids, and carrier molecules (fulvic acids). See, Ghosal, S., et al., “Shilajit Part 1—Chemical constituents,” J. Pharm. Sci. (1976) 65:772-3; Ghosal, S., et al., “Shilajit Part 7—Chemistry of Shilajit, an immunomodulatory ayurvedic rasayana,” Pure Appl. Chem. (IUPAC) (1990) 62:1285-8; Ghosal, S., et al., “The core structure of Shilajit humus,” Soil Biol. Biochem. (1992) 23:673-80; and U.S. Pat. Nos. 6,440,436 and 6,869,612 (and references cited therein); all hereby incorporated by reference herein.
Shilajit (PrimaVie®) finds extensive use in Ayurveda, for diverse clinical conditions. For centuries people living in the isolated villages in Himalaya and adjoining regions have used Shilajit alone, or in combination with, other plant remedies to prevent and combat problems with diabetes (Tiwari, V. P., et al., “An interpretation of Ayurvedica findings on Shilajit,” J. Res. Indigenous Med. (1973) 8:57). Moreover being an antioxidant it will prevent damage to the pancreatic islet cell induced by the cytotoxic oxygen radicals (Bhattacharya S. K., “Shilajit attenuates streptozotocin induced diabetes mellitus and decrease in pancreatic islet superoxide dismutase activity in rats,” Phytother. Res. (1995) 9:41-4; Bhattacharya S. K., “Effects of Shilajit on biogenic free radicals,” Phytother. Res. (1995) 9:56-9; and Ghosal, S., et al., “Interaction of Shilajit with biogenic free radicals,” Indian J. Chem. (1995) 34B:596-602). It has been proposed that the derangement of glucose, fat and protein metabolism during diabetes, results in development of hyperlipidemia. In one study, Shilajit produced significant beneficial effects on lipid profile in rats (Trivedi N. A., et al., “Effect of Shilajit on blood glucose and lipid profile in alloxan-induced diabetic rats,” Indian J. Pharmacol. (2004) 36(6):373-376). Further, Chromium 3+(Cr 3+) helps insulin metabolize fat, turn protein into muscle, and convert sugar into energy. Chromium-activated insulin considerably increases the amount of blood sugar available for energy production. Some of the other chromium compounds available as supplements are Chromium chloride, Chromium picolinate, Chromium polynicotinate, and Chromium dinicocysteinate.
Crominex®3+, which is a complex of chromium with the polyphenolic compounds of Phyllanthus emblica and Shilajit, as described herein in embodiments of the present invention surprisingly exhibited improvement in endothelial function and blood lipid profile in type 2 diabetics as well as individuals with symptoms of metabolic syndrome, although it contains very small amounts of Phyllanthus emblica and Shilajit (3 mg of each per 200 mcg dose of chromium, and 6 mg each per 400 mcg dose of chromium, respectively). Both Phyllanthus emblica and Shilajit are usually effective in doses of 250 or 500 mg per dose. For example, U.S. Pat. No. 8,962,576 describes a composition and method of improving endothelial function and cardiovascular health using Phyllanthus emblica extract at 250 mg and 500 mg twice a day dosing (which is equivalent to 500 mg and 1000 mg per day). Similarly, U.S. Patent Application Publication US2014/0079729A1 describes a method of improving endothelial function and decreasing cardiovascular morbidity using Shilajit at 250 mg twice a day dosing (which is equivalent to 500 mg per day). However, a combination of Chromium, Phyllanthus emblica extract and Shilajit surprisingly exhibited effectiveness in improving endothelial function and cardiovascular risk parameters, although the concentrations of Phyllanthus emblica extract and Shilajit are very low as discussed above and described herein.
Thus, it would be advantageous to have a composition with small amounts of chromium and small amounts of Phyllanthus emblica and Shilajit which would significantly improve endothelial function and cardiovascular risk factors.